Functional dissection of Drosophila homeodomain transcription factors required for development of the body plan.

制定身体计划所需的果蝇同源域转录因子的功能解剖。

• 批准号: RGPIN-2015-06356
• 负责人: PercivalSmith, Anthony
• 金额: $ 3.28万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614101
• 关键词: Functional; dissection; Drosophila; homeodomain; transcription

Nearly all animals exhibit some form of segmentation along the anterior-posterior (head to tail) axis.  An example of segmentation of the human body plan is the backbone; where each vertebra represents an individual segment and has a unique structure or morphology.  I am interested in two general questions: first how the normal number of segments is established; and second how a segment is assigned a unique morphology?  To address this rigorously, I use the Drosophila melanogaster (fruit fly) insect model system where the body plan is divided into 14 segmental units (parasegments) along the anterior-posterior axis.  The Drosophila fushi tarazu gene (ftz) encodes a protein FTZ required for determining the number of segments that form during development, and the proboscipedia (pb) and Sex combs reduced (Scr) genes encode proteins PB and SCR that work alone or together to determine the unique identities of 3 segments (maxillary, labial, and first thoracic).  All three proteins share a DNA-binding protein domain called the homeodomain (HD).  HD-containing proteins (HOX) are transcription factors that regulate the transcription of genes, the process that converts information stored in DNA to RNA that can be read by the protein synthesis machinery.  Even though many of the genes regulated by FTZ, PB and SCR have been identified and extensively characterized, there is a lack of knowledge about how these transcription factors work to bring about changes in the pattern of gene transcription.  One key element lacking is a complete description of the functional domain structure of these proteins.  HOX transcription factors have been analyzed for over twenty years, but the mapping of the functional domains has proven difficult.  In recent years, my group and others have found that HD-containing proteins are composed of small peptide motifs that make small contributions to overall activity.  We are interested in a deeper dissection of the roles of these small motifs in development. This knowledge will greatly enhance our understanding of the mechanistic logic behind the segmentation of the insect body plan, and as HOX proteins are also used during the segmentation of the vertebrate (human) body plan, this work has general application to the understanding of the developmental process in general.  Furthermore, as HOX proteins are examples of transcription factors, this work in flies provides important insights of general biological significance and application on mechanisms that control gene expression.  Since, when you look around at the natural world it is the control of gene expression that makes the grass green, blood red and daffodils yellow; the control of gene expression is fundamental to all Biology.

几乎所有的动物都表现出沿沿着前后（头到尾）轴的某种形式的分割。人体计划分割的一个例子是脊柱;其中每个椎骨代表一个单独的节段，并具有独特的结构或形态。我感兴趣的两个一般性问题：第一，节段的正常数量是如何建立的;第二，节段是如何分配一个独特的形态？ 为了严格地解决这个问题，我用果蝇（果蝇）昆虫模型系统，其中身体平面被分成14个节段单元果蝇fushi tarazu基因（ftz）编码蛋白质FTZ，所述蛋白质FTZ是确定在发育期间形成的节段的数量所需的，而长鼻足（pb）和性梳减少（Scr）基因编码蛋白质PB和SCR，它们单独或共同作用以确定3个片段的独特身份所有三种蛋白质共享称为同源结构域（HD）的DNA结合蛋白结构域。 含HD-containing蛋白（HOX）是调控基因转录的转录因子，该过程将储存在DNA中的信息转化为可由蛋白质合成机器读取的RNA。尽管许多受FTZ、PB和SCR调控的基因已被鉴定和广泛表征，目前对这些转录因子如何改变基因转录模式的认识还很缺乏，其中一个关键因素是对功能域的完整描述HOX转录因子已经被分析了二十多年，但是功能域的定位已经被证明是困难的。近年来，我的小组和其他人发现含HD的蛋白质由对整体活性贡献很小的小肽基序组成。 我们对这些小基序在发育中的作用有更深层次的解剖感兴趣。这些知识将极大地增强我们对昆虫身体平面分割背后的机械逻辑的理解，并且由于HOX蛋白也用于脊椎动物（人类）身体平面的分割，这项工作对理解一般发育过程具有普遍的应用。此外，由于HOX蛋白是转录因子的实例，因此在果蝇中的这项工作提供了关于控制基因表达的机制的一般生物学意义和应用的重要见解。 因为，当你环顾自然界时，正是基因表达的控制使草绿色，血红色和水仙花黄色;基因表达的控制是所有生物学的基础。